Gliomas, the most frequent primary brain tumors in adults, are debilitating malignancies that arise from the transformation of astrocytes or glial precursors (Singh et al., 2004, Nature 432, 396-401). The most common and aggressive form of glioma, glioblastoma multiforme (GBM), is associated with a median survival of less than 12 months with a <6% survival rate following 24 months (Legler et al., 1999, J. Natl. Cancer Inst. 91, 1382-1390). GBM commonly over-express epidermal growth factor receptor and platelet-derived growth factor receptor and contain mutations in the phosphatase and tensin homolog and p53 genes, which contribute to phosphoinositide-3-kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase activation and potentially regulate transcription factors including AP-1 and NFκB.
Intracerebral hemorrhage (ICH) induces 50-60% mortality within the first year and is associated with long-term disability in many survivors. Primary ICH may be caused by the rupture of small vessels damaged by chronic hypertension or amyloid angiopathy. This can lead to the accumulation of erythrocytes within the parenchyma and the formation of a space-occupying hematoma. Hematoma volume directly correlates with neurological outcome, supporting clot evacuation as a strategy to attenuate brain injury and improve patient prognosis. Unfortunately, a limited number of suitable surgical candidates and/or unfavorable size/location of the mass lesion may restrict the utility of neurosurgical intervention. As such, treatment options remain largely supportive, reinforcing the notion that ICH is the least treatable form of stroke and stressing the need for novel therapeutic approaches. Studies have shown early phase predictive markers of acute hematoma growth include an inflammatory reaction and neurological deterioration in ICH patients. The activation of the pro-inflammatory transcription factor, NFκB, increased the expression of inflammatory mediators associated with cell death, increased blood-brain barrier (BBB) permeability, and induced the development of vasogenic edema in ICH subjects. Thus, a reduction in inflammatory activation may limit neurovascular injury and improve clinical outcomes following ICH.
Curcumin (diferuloylmethane), a naturally occurring polyphenol derived from the root of the rhizome, Curcuma longa, possesses anti-inflammatory and antioxidant properties, in part via a reduction in AP-1 and NFκB activity. Curcumin recently entered Phase I clinical trials for the treatment of several high-risk cancers (Cheng et al., 2001, Oncogene, 19, 4936-4940), and a recent study shows curcumin may exert multiple beneficial effects in glioma cells, including inhibition of cellular growth, invasion, and angiogenesis (Dhandapani et al., 2007, J. Neurochem., 102, 522-538).
Curcumin has been safely consumed by humans for centuries, including use as an anti-inflammatory agent in Ayurveda, an ancient Indian system of medicine. Recent clinical trials also demonstrated that oral administration of curcumin resulted in bioactivity with minimal adverse effects, even when administered at high doses. However, clinical trials in humans have indicated that the systemic bioavailability of orally administered curcumin is relatively low (Anand et al., Mol. Pharm., 2007, 4, 807-818) and that mostly metabolites of curcumin, instead of curcumin itself, are detected in plasma or serum following oral consumption (Baum et al., J. Clin. Psychopharmacol., 2008, 28, 110-113; Lao et al., BMC Complement Altern. Med., 2006, 6, 10). In the intestine and liver, curcumin is readily conjugated to form curcumin glucuronides and curcumin sulfates or, alternately, reduced to hexahydrocurcumin.
It is an object of this invention to provide compounds and compositions that have greater systemic bioavailability than curcumin.
It is another object of this invention to provide compounds, compositions and methods that treat intracerebral hemorrhage.
It is another object of this invention to compounds, compositions and methods that prevent and treat malignant gliomas.
It is also another object of the present invention to provide compounds, compositions and methods for the treatment of diseases or conditions associated with NFκB activity.